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There are currently two major methods of sequencing DNA in use. Both work by using a DNA polymerase (an enzyme that copies DNA) to make a new copy of the DNA in question. Sanger sequencing, which is used for most genome projects, works by randomly stopping a small fraction of the reactions at each base, with the last base being tagged by a fluorescent molecule. Based on the color of that molecule, each base can be identified. This works very well for sequences up to 800 bases long, but is limited by the need to stop some of the reactions at each base; in the end, there are just too few reactions around to provide readable sequence past 800 bases.

The big alternative, pyrosequencing, has been used for ancient DNA because it is very efficient; all reactions keep going after each base is added. Unfortunately, all four bases are detected via the same color light, and stretches of identical bases are judged based on how bright the light is. As a result it's not incredibly accurate and only works well for short strands. Some chemists, however, may have found a way (open access) to get around the limitations in each of these systems. With the new method, every reaction stops at every base, but then starts up again; meanwhile, each type of base is identified by a unique color.

They achieved this by synthesizing the four DNA bases so that each was linked to a fluorescent molecule of a different color in a way that blocks DNA polymerases from extending the reaction any further. When added to a reaction, all the DNA molecules add just a single base and, as a result, all of them glow with a single color. The key difference, however, is that adding a specific chemical can pop the fluorescent molecule off, and leave the DNA in a state where the polymerase can add another base. Using the same mixture of bases, the whole collection of DNA molecules can move one base further down, and will again glow with a single appropriate color. This allows the reaction to cycle, and work its way down the DNA strand, one base (and color) at a time.

The researchers involved had to run the reaction through this cycle manually, but they still managed to get 20 bases of very clean sequence out of it. In theory, since each DNA molecule participates in every reading of sequence, the efficiency should allow it to work with very small DNA samples (unlike Sanger), while having none of the accuracy issues of pyrosequencing. The authors suggest that with some automation and optimizations, there's no telling how far this technique can take a sequence read. I'd imagine that they've already arranged for a company to find out.

One last cool aspect of the work: about halfway through writing it up, I looked at the list of authors and realized that the senior author taught me Physical Chemistry back when I was in college.